tbuckley/cabot-search huggingface dataset:
Purine and purinergic receptors in health and disease
Authors: Yanling Ai, Hengyi Wang, Lu Liu, Yulin Qi, Shiyun Tang, Jianyuan Tang, Nianzhi Chen
Journal: MedComm (2023)

Purines and purinergic receptors are widely distributed throughout the human body. Purine molecules within cells play crucial roles in regulating energy metabolism and other cellular processes, while extracellular purines transmit signals through specific purinergic receptors. The ubiquitous purinergic signaling maintains normal neural excitability, digestion and absorption, respiratory movement, and other complex physiological activities, and participates in cell proliferation, differentiation, migration, and death. Pathological dysregulation of purinergic signaling can result in the development of various diseases, including neurodegeneration, inflammatory reactions, and malignant tumors. The dysregulation or dysfunction of purines and purinergic receptors has been demonstrated to be closely associated with tumor progression. Compared with other subtypes of purinergic receptors, the P2X7 receptor (P2X7R) exhibits distinct characteristics (i.e., a low affinity for ATP, dual functionality upon activation, the mediation of ion channels, and nonselective pores formation) and is considered a promising target for antitumor therapy, particularly in patients with poor response to immunotherapy This review summarizes the physiological and pathological significance of purinergic signaling and purinergic receptors, analyzes their complex relationship with tumors, and proposes potential antitumor immunotherapy strategies from tumor P2X7R inhibition, tumor P2X7R overactivation, and host P2X7R activation. This review provides a reference for clinical immunotherapy and mechanism investigation.
<i>Lactobacillus johnsonii</i> N6.2 phospholipids induce immature-like dendritic cells with a migratory-regulatory-like transcriptional signature
Authors: Alexandra E. Cuaycal, Leandro Dias Teixeira, Graciela L. Lorca, Claudio F. Gonzalez
Journal: Gut Microbes (2023)

Shifts in the gut microbiota composition, called dysbiosis, have been directly associated with acute and chronic diseases. However, the underlying biological systems connecting gut dysbiosis to systemic inflammatory pathologies are not well understood. Phospholipids (PLs) act as precursors of both, bioactive inflammatory and resolving mediators. Their dysregulation is associated with chronic diseases including cancer. Gut microbial-derived lipids are structurally unique and capable of modulating host's immunity. Lactobacillus johnsonii N6.2 is a Gram-positive gut symbiont with probiotic characteristics. L. johnsonii N6.2 reduces the incidence of autoimmunity in animal models of Type 1 Diabetes and improves general wellness in healthy volunteers by promoting, in part, local and systemic anti-inflammatory responses. By utilizing bioassay-guided fractionation methods with bone marrow-derived dendritic cells (BMDCs), we report here that L. johnsonii N6.2 purified lipids induce a transcriptional signature that resembles that of migratory (mig) DCs. RNAseq-based analysis showed that BMDCs stimulated with L. johnsonii N6.2 total lipids upregulate maturation-mig related genes Cd86, Cd40, Ccr7, Icam1 along with immunoregulatory genes including Itgb8, Nfkbiz, Jag1, Adora2a, IL2ra, Arg1, and Cd274. Quantitative reverse transcription (qRT)-PCR analysis indicated that PLs are the bioactive lipids triggering the BMDCs response. Antibody-blocking of surface Toll-like receptor (TLR)2 resulted in boosted PL-mediated upregulation of pro-inflammatory Il6. Chemical inhibition of the IKKα kinase from the non-canonical NF-κB pathway specifically restricted upregulation of Il6 and Tnf. Phenotypically, PL-stimulated BMDCs displayed an immature like-phenotype with significantly increased surface ICAM-1. This study provides insight into the immunoregulatory capacity of Gram-positive, gut microbial-derived phospholipids on innate immune responses.
Secondary-type mutations do not impact outcome in NPM1-mutated acute myeloid leukemia – implications for the European LeukemiaNet risk classification
Authors: Jan-Niklas Eckardt, Marius Bill, Christian Rausch, Klaus Metzeler, Karsten Spiekermann, Sebastian Stasik, Tim Sauer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H. Brümmendorf, Utz Krug, Bernhard Wörmann, Wolfgang Hiddemann, Dennis Görlich, Cristina Sauerland, Björn Steffen, Hermann Einsele, Andreas Neubauer, Andreas Burchert, Kerstin Schäfer-Eckart, Wolfgang E. Berdel, Christoph Schliemann, Stefan W. Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Leo Ruhnke, Johannes Schetelig, Jan Moritz Middeke, Hubert Serve, Claudia D. Baldus, Uwe Platzbecker, Carsten Müller-Tidow, Martin Bornhäuser, Tobias Herold, Christian Thiede, Christoph Röllig
Journal: Leukemia (2023)
Individualized tumor-informed circulating tumor DNA analysis for postoperative monitoring of non-small cell lung cancer
Authors: Kezhong Chen, Fan Yang, Haifeng Shen, Chenyang Wang, Xi Li, Olga Chervova, Shuailai Wu, Fujun Qiu, Di Peng, Xin Zhu, Shannon Chuai, Stephan Beck, Nnennaya Kanu, David Carbone, Zhihong Zhang, Jun Wang
Journal: Cancer Cell (2023)
PARP-1 improves leukemia outcomes by inducing parthanatos during chemotherapy
Authors: Bruktawit Maru, Alessandra Messikommer, Linhui Huang, Katja Seipel, Olivia Kovecses, Peter J.M. Valk, Alexandre P.A. Theocharides, Francois E. Mercier, Thomas Pabst, Maureen McKeague, Nathan W. Luedtke
Journal: Cell Reports Medicine (2023)

Previous chemotherapy research has focused almost exclusively on apoptosis. Here, a standard frontline drug combination of cytarabine and idarubicin induces distinct features of caspase-independent, poly(ADP-ribose) polymerase 1 (PARP-1)-mediated programmed cell death "parthanatos" in acute myeloid leukemia (AML) cell lines (n = 3/10 tested), peripheral blood mononuclear cells from healthy human donors (n = 10/10 tested), and primary cell samples from patients with AML (n = 18/39 tested, French-American-British subtypes M4 and M5). A 3-fold improvement in survival rates is observed in the parthanatos-positive versus -negative patient groups (hazard ratio [HR] = 0.28-0.37, p = 0.002-0.046). Manipulation of PARP-1 activity in parthanatos-competent cells reveals higher drug sensitivity in cells that have basal PARP-1 levels as compared with those subjected to PARP-1 overexpression or suppression. The same trends are observed in RNA expression databases and support the conclusion that PARP-1 can have optimal levels for favorable chemotherapeutic responses.
Small intestine vs. colon ecology and physiology: Why it matters in probiotic administration
Authors: Benjamin Anderschou Holbech Jensen, Marc Heyndrickx, Daisy Jonkers, Alan Mackie, Sam Millet, Malwina Naghibi, Simone Isling Pærregaard, Bruno Pot, Delphine Saulnier, Christian Sina, Luc Gerardus Willibrordus Sterkman, Pieter Van den Abbeele, Naomi Vita Venlet, Erwin G. Zoetendal, Arthur Constantijn Ouwehand
Journal: Cell Reports Medicine (2023)

Research on gut microbiota has generally focused on fecal samples, representing luminal content of the large intestine. However, nutrient uptake is restricted to the small intestine. Abundant immune cell populations at this anatomical site combined with diminished mucus secretion and looser junctions (partly to allow for more efficient fluid and nutrient absorption) also results in intimate host-microbe interactions despite more rapid transit. It is thus crucial to dissect key differences in both ecology and physiology between small and large intestine to better leverage the immense potential of human gut microbiota imprinting, including probiotic engraftment at biological sensible niches. Here, we provide a detailed review unfolding how the physiological and anatomical differences between the small and large intestine affect gut microbiota composition, function, and plasticity. This information is key to understanding how gut microbiota manipulation, including probiotic administration, may strain-dependently transform host-microbe interactions at defined locations.
The skeletal muscle metaboreflex: a novel driver of ventilation, dyspnoea and pulmonary haemodynamics during exercise in pulmonary arterial hypertension
Authors: Michael J. Plunkett, Ana Luiza C. Sayegh, Tanya J. McWilliams, Sasiharan Sithamparanathan, Julian F.R. Paton, James P. Fisher
Journal: European Respiratory Journal (2023)

Impairment of exercise capacity, predominately limited symptomatically by dyspnoea [1], affects most patients with pulmonary arterial hypertension (PAH) despite current therapies [2] with significant implication for patients, adversely impairing health-related quality of life [3] and clinical prognosis [4]. However, the underpinning physiologic mechanisms behind dyspnoea and exercise limitation remain incompletely understood. Skeletal muscle metabolic and microcirculatory deficits are present in PAH [2] and likely lead to earlier and more pronounced accumulation of metabolites during exercise. We hypothesised that this would augment the activation of group III/IV afferents responsive to metabolites present in exercising limb muscles ( i.e. , muscle metaboreflex), and provide a novel driver for hyperventilation [5], pulmonary arterial pressure [6] and sensations of dyspnoea [7] in PAH. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Diagnostic performance of circulating biomarkers for non-alcoholic steatohepatitis
Authors: Arun J. Sanyal, Sudha S. Shankar, Katherine P. Yates, James Bolognese, Erika Daly, Clayton A. Dehn, Brent Neuschwander-Tetri, Kris Kowdley, Raj Vuppalanchi, Cynthia Behling, James Tonascia, Anthony Samir, Claude Sirlin, Sarah P. Sherlock, Kathryn Fowler, Helen Heymann, Tania N. Kamphaus, Rohit Loomba, Roberto A. Calle
Journal: Nature Medicine (2023)

Abstract There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort ( n = 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages &gt;2, &gt;3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78–0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.
Scaffolding cooperation in human groups with deep reinforcement learning
Authors: Kevin R. McKee, Andrea Tacchetti, Michiel A. Bakker, Jan Balaguer, Lucy Campbell-Gillingham, Richard Everett, Matthew Botvinick
Journal: Nature Human Behaviour (2023)

Abstract Effective approaches to encouraging group cooperation are still an open challenge. Here we apply recent advances in deep learning to structure networks of human participants playing a group cooperation game. We leverage deep reinforcement learning and simulation methods to train a ‘social planner’ capable of making recommendations to create or break connections between group members. The strategy that it develops succeeds at encouraging pro-sociality in networks of human participants ( N = 208 participants in 13 groups) playing for real monetary stakes. Under the social planner, groups finished the game with an average cooperation rate of 77.7%, compared with 42.8% in static networks ( N = 176 in 11 groups). In contrast to prior strategies that separate defectors from cooperators (tested here with N = 384 in 24 groups), the social planner learns to take a conciliatory approach to defectors, encouraging them to act pro-socially by moving them to small highly cooperative neighbourhoods.
Dietary potassium stimulates Ppp1Ca-Ppp1r1a dephosphorylation of kidney NaCl cotransporter and reduces blood pressure
Authors: P. Richard Grimm, Anamaria Tatomir, Lena L. Rosenbaek, Bo Young Kim, Dimin Li, Eric J. Delpire, Robert A. Fenton, Paul A. Welling
Journal: Journal of Clinical Investigation (2023)

Consumption of low dietary potassium, common with ultra-processed foods, activates the thiazide-sensitive sodium chloride cotransporter (NCC) via the WNK-SPAK kinase pathway to induce salt retention and elevate blood pressure (BP). However, it remains unclear how high potassium "DASH-like" diets inactivate the cotransporter and whether this decreases BP. A transcriptomic screen identified Ppp1C⍺, encoding PP1A, as a potassium up-regulated gene, and its negative regulator, Ppp1r1a, as a potassium-suppressed gene in the kidney. PP1A directly binds to and dephosphorylates NCC when extracellular potassium is elevated. Using mice genetically engineered to constitutively activate the NCC-regulatory kinase SPAK and thereby eliminate the effects of the WNK-SPAK kinase cascade, we confirmed that PP1A dephosphorylates NCC directly in a potassium-regulated manner. Prior adaptation to a high potassium diet was required to maximally dephosphorylate NCC and lower BP in the constitutively active SPAK mice, and this was associated with potassium-dependent suppression of Ppp1r1a, and dephosphorylation of its cognate protein, Inhibitory Subunit 1 (I1). In conclusion, potassium-dependent activation of PP1A and inhibition of I1 drives NCC dephosphorylation, providing a mechanism to explain how high dietary K+ lowers BP. Shifting signaling of PP1A in favor of activation of WNK-SPAK may provide an improved therapeutic approach for treating salt-sensitive hypertension.
Author Correction: Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Authors: Jing Hua Zhao, David Stacey, Niclas Eriksson, Erin Macdonald-Dunlop, Åsa K. Hedman, Anette Kalnapenkis, Stefan Enroth, Domenico Cozzetto, Jonathan Digby-Bell, Jonathan Marten, Lasse Folkersen, Christian Herder, Lina Jonsson, Sarah E. Bergen, Christian Gieger, Elise J. Needham, Praveen Surendran, Andres Metspalu, Lili Milani, Reedik Mägi, Mari Nelis, Georgi Hudjašov, Dirk S. Paul, Ozren Polasek, Barbara Thorand, Harald Grallert, Michael Roden, Urmo Võsa, Tonu Esko, Caroline Hayward, Åsa Johansson, Ulf Gyllensten, Nick Powell, Oskar Hansson, Niklas Mattsson-Carlgren, Peter K. Joshi, John Danesh, Leonid Padyukov, Lars Klareskog, Mikael Landén, James F. Wilson, Agneta Siegbahn, Lars Wallentin, Anders Mälarstig, Adam S. Butterworth, James E. Peters
Journal: Nature Immunology (2023)

Genetics of circulating inflammatory proteins identifies drivers of immunemediated disease risk and therapeutic targetsCirculating proteins have important functions in inflammation and a broad range of diseases.To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants.We identified 180 pQTLs (59 cis, 121 trans).Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis.Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease.MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC.These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
CXCR6 orchestrates brain CD8+ T cell residency and limits mouse Alzheimer’s disease pathology
Authors: Wei Su, Jordy Saravia, Isabel Risch, Sherri Rankin, Cliff Guy, Nicole M. Chapman, Hao Shi, Yu Sun, Anil KC, Wei Li, Hongling Huang, Seon Ah Lim, Haoran Hu, Yan Wang, Danting Liu, Yun Jiao, Ping-Chung Chen, Hadeer Soliman, Koon-Kiu Yan, Jonathan Zhang, Peter Vogel, Xueyan Liu, Geidy E. Serrano, Thomas G. Beach, Jiyang Yu, Junmin Peng, Hongbo Chi
Journal: Nature Immunology (2023)
Alleviating symptoms of neurodegenerative disorders by astrocyte-specific overexpression of TMEM164 in mice
Authors: Liansheng Zhang, Zhiheng Jia, Qiang Wu, Tao Bai, Bo Wang, Xinde Hu, Tianwen Li, Xingyu Liu, Jiqiang Fu, Yuelei Chen, Xiaoyan Ding, Zhen Liu, Zhengzheng Xu, Haibo Zhou
Journal: Nature Metabolism (2023)
World’s human migration patterns in 2000–2019 unveiled by high-resolution data
Authors: Venla Niva, Alexander Horton, Vili Virkki, Matias Heino, Maria Kosonen, Marko Kallio, Pekka Kinnunen, Guy J. Abel, Raya Muttarak, Maija Taka, Olli Varis, Matti Kummu
Journal: Nature Human Behaviour (2023)

Abstract Despite being a topical issue in public debate and on the political agenda for many countries, a global-scale, high-resolution quantification of migration and its major drivers for the recent decades remained missing. We created a global dataset of annual net migration between 2000 and 2019 (~10 km grid, covering the areas of 216 countries or sovereign states), based on reported and downscaled subnational birth (2,555 administrative units) and death (2,067 administrative units) rates. We show that, globally, around 50% of the world’s urban population lived in areas where migration accelerated urban population growth, while a third of the global population lived in provinces where rural areas experienced positive net migration. Finally, we show that, globally, socioeconomic factors are more strongly associated with migration patterns than climatic factors. While our method is dependent on census data, incurring notable uncertainties in regions where census data coverage or quality is low, we were able to capture migration patterns not only between but also within countries, as well as by socioeconomic and geophysical zonings. Our results highlight the importance of subnational analysis of migration—a necessity for policy design, international cooperation and shared responsibility for managing internal and international migration.
Persister cell phenotypes contribute to poor patient outcomes after neoadjuvant chemotherapy in PDAC
Authors: Xu Zhou, Jingyu An, Roma Kurilov, Benedikt Brors, Kai Hu, Teresa Peccerella, Stephanie Roessler, Katrin Pfütze, Angela Schulz, Stephan Wolf, Nicolas Hohmann, Dirk Theile, Max Sauter, Jürgen Burhenne, Shigenori Ei, Ulrike Heger, Oliver Strobel, Simon T. Barry, Christoph Springfeld, Christine Tjaden, Frank Bergmann, Markus Büchler, Thilo Hackert, Franco Fortunato, John P. Neoptolemos, Peter Bailey
Journal: Nature Cancer (2023)

Neoadjuvant chemotherapy can improve the survival of individuals with borderline and unresectable pancreatic ductal adenocarcinoma; however, heterogeneous responses to chemotherapy remain a significant clinical challenge. Here, we performed RNA sequencing (n = 97) and multiplexed immunofluorescence (n = 122) on chemo-naive and postchemotherapy (post-CTX) resected patient samples (chemoradiotherapy excluded) to define the impact of neoadjuvant chemotherapy. Transcriptome analysis combined with high-resolution mapping of whole-tissue sections identified GATA6 (classical), KRT17 (basal-like) and cytochrome P450 3A (CYP3A) coexpressing cells that were preferentially enriched in post-CTX resected samples. The persistence of GATA6
Senolytic therapy in mild Alzheimer’s disease: a phase 1 feasibility trial
Authors: Mitzi M. Gonzales, Valentina R. Garbarino, Tiffany F. Kautz, Juan Pablo Palavicini, Marisa Lopez-Cruzan, Shiva Kazempour Dehkordi, Julia J. Mathews, Habil Zare, Peng Xu, Bin Zhang, Crystal Franklin, Mohamad Habes, Suzanne Craft, Ronald C. Petersen, Tamara Tchkonia, James L. Kirkland, Arash Salardini, Sudha Seshadri, Nicolas Musi, Miranda E. Orr
Journal: Nature Medicine (2023)
Synthetically glycosylated antigens for the antigen-specific suppression of established immune responses
Authors: Andrew C. Tremain, Rachel P. Wallace, Kristen M. Lorentz, Thomas B. Thornley, Jennifer T. Antane, Michal R. Raczy, Joseph W. Reda, Aaron T. Alpar, Anna J. Slezak, Elyse A. Watkins, Chitavi D. Maulloo, Erica Budina, Ani Solanki, Mindy Nguyen, David J. Bischoff, Jamie L. Harrington, Rabinarayan Mishra, Gregory P. Conley, Romain Marlin, Nathalie Dereuddre-Bosquet, Anne-Sophie Gallouët, Roger LeGrand, D. Scott Wilson, Stephan Kontos, Jeffrey A. Hubbell
Journal: Nature Biomedical Engineering (2023)
<i>Notes from the Field:</i> Gastrointestinal Illness Among Hikers on the Pacific Crest Trail — Washington, August–October 2022
Authors: Arran Hamlet, Katherine Begley, Shanna Miko, Laurie Stewart, Waimon Tellier, Joenice Gonzalez-De Leon, Hillary Booth, Soyeon Lippman, Amy Kahler, Alexis Roundtree, April Hatada, Scott Lindquist, Beth Melius, Marcia Goldoft, Mia Mattioli, Michelle Holshue
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

On August 26, 2022, the Washington State Department of Health received informal reports of numerous Pacific Crest Trail hikers with acute gastroenteritis (AGE).The Pacific Crest Trail stretches 2,650 miles from California to Washington, attracting hikers from around the world (1).An investigation of social media postings on September 5 found 27 reports of AGE by Washington Pacific Crest Trail hikers during the previous month, 26 of whom provided information about symptom onset date (Figure).Numerous additional reports without a specific date were found, suggesting that that AGE was occurring during the 2022 hiking season.